A descriptive summary
prepared by the Bloom’s Syndrome Registry for registered persons and their
families.

Definition

Bloom’s syndrome
(BS) is a rare disorder the two main features of which are the following:

(i)Unusually small size, both before and after birth. During infancy and
early childhood, fat tissue is exceptionally sparse, an unusual and unexplained
lack of interest in feeding doubtless contributing to this. Body proportions
are approximately normal as is muscular development, often giving the affected child
unusual agility and grace. When grown, men with BS are taller than women,
occasionally reaching slightly over 5 feet.

(ii)A sun-sensitive, red, skin lesion affecting the face almost exclusively.
It varies in severity from mild to severe. Sometimes
the backs of the hands and forearms are affected mildly.

Although
the general health is good, persons with BS are more likely than others to
develop the following:

(i)Infections of the middle ear and lung (pneumonia), the latter sometimes
progressing to bronchiectasis and chronic lung disease.

(ii)Diabetes, that in many respects resembles the standard adult-onset type
but appearing earlier in life in BS than in the general population.

(iii)Neoplasms (tumors), both benign and malignant, of the standard types and
sites that affect other people but in BS arising unusually early in life.

Regarding
reproductive ability, puberty is at the usual age, and sexual interests and
activity are normal. Several women with BS have had children, all normal. The
menopause is unusually early. All men appropriately tested have been
infertile.

Although mental
deficiency is not a regular feature of BS, some affected persons have been
retarded. Many have exhibited a poorly defined restriction on learning and the
development of outside interests. However, most affected persons do obtain
reasonably good educations, develop friendships, and integrate well in society.
A few have excelled in school and obtained higher degrees.

Cause

BS is a genetic
trait. The affected person has inherited from each of his/her parents a
mutation in the Bloom’s syndrome gene, i.e., he/she has two mutant BS genes, no
normal. The BS gene is named BLM.
(Note. The designations for human genes are printed in italics, e.g., BLM, the proteins which they encode in roman typeface,
e.g. BLM, which is the BS protein.) Persons who carry a mutated BLM in single “dose” – who in genetic terms are
heterozygotes -- are healthy and of normal height. Once a couple has had a
child with BS, thereby demonstrating that each partner is heterozygous for a
mutated BLM, the risk of BS for
each pregnancy is 1 in 4 (25%). Prenatal diagnosis is possible.

More than 60
different BS-causing mutations of BLM
have been detected. They obviously have arisen at various times in the distant
past and been transmitted through perfectly healthy people for untold numbers
of generations. The great rarity of the syndrome itself is because very few
people carry a mutation of BLM.
In the Ashkenazi Jewish population, one particular BS-causing mutation,
referred to as blmAsh,
did reach a relatively high frequency because of the unusual population
structure of Eastern European Jewry. Today approximately 1% of Ashkenazi
persons carries blmAsh,
which explains why BS is relatively less rare in that group than in any other
identified so far.

What is known
about BLM, the normal BS protein? It has DNA helicase activity; i.e., the
ability to unwind – to “open up” -- the double helical structure of DNA.
However, a large number of DNA helicases exist in human cells, and in exactly
which DNA transaction(s) BLM is active remains the subject of investigation in
several basic research laboratories. Nevertheless, it is obvious that this evolutionarily
highly conserved protein plays a very important role in maintaining the
stability of the genetic material itself, i.e., of the DNA, of preserving the
fidelity of the genome; when a cell lacks BLM’s function (the situation in
every cell of the person with BS), many more mutations arise than in other
people. In the cells of persons with BS the chromosomes can be seen to break
and rearrange more often than in cells of others; such microscopically visible
chromosome mutations are of particular importance in relation to BS’s cancer
proneness.

What is known about how/why the lack of a normal BLM results in clinical “Bloom’s syndrome”?

(i)The explanation is not yet known for the syndrome’s main feature, the unusually
small size. Obviously the lack of BLM in some way results in there being
proportionally fewer than normal cells in each tissue and organ of the body.

(ii)The proneness to serious middle ear and lung infections suggests that
BLM is required for the optimum functioning of cell lineages that are concerned
with immunity. However, gastro-esophageal reflus (see below) could also be
responsible.

(iii)The reason diabetes appears more frequently and earlier in BS than in
others is unknown. The striking sparseness of fat tissue early in life
conceivably is in some way responsible.

(iv)In contrast, the cancer predisposition of BS is explained: the increased number of mutations that
are arising spontaneously in the various cells of the body is responsible.
When a mutation occurs in one of the classes of genes known as
growth-suppressors and proto-oncogenes, whose important normal functions are to
regulate how often a cell will divide or determine how long it will live,
normal control over those important matters is lost; and, the consequence is an
abnormal degree of proliferation of that cell and its progeny – neoplasia.
(If the resulting neoplasm threatens the life of the person in whom it arises,
it is said to be malignant – a cancer.)

(Note. The reader of the preceding section will note,
possibly with surprise, that of the four major features/complications of BS,
the basis for only the fourth is understood to any significant degree. Those
238 persons with BS, and their families, who have participated in the over-four-decades-long
program to define and understand BS – the Bloom’s Syndrome Registry
– have understood two important things, first, that rare BS is a valuable
model from which clinical investigators
and basic scientists can learn about important health matters such as the
determination of size and immunity, and about important diseases such as
cancer, diabetes, and chronic lung disease; and, second, that with the gradual
accrual of such understanding, they themselves may benefit directly-- and often
do.)

Management

(i)No treatment is available to stabilize the genome in the cells of
persons with BS – i.e., that will correct the tendency for excessive
numbers of mutations to arise.

(ii)Medical intervention aimed at improving growth in BS has been
unsuccessful. Growth hormone production is normal in BS, and its
administration has had little if any effect. Infants and young children with
BS are notoriously poor eaters; sometimes a condition known as
gastro-esophageal reflux has been shown to be responsible. If demonstrable,
management of the reflux can be attempted. Non-volitional feeding (as, for
example, by the surgical placement of a tube into the upper intestinal tract for
supplementary nocturnal feeding) can increase fat deposits in infants with BS; however,
an effect of such treatment on linear growth (height) is minimal or absent.

(iii)The facial skin lesion demands protection from the sun by the avoidance
of sunlight whenever possible, and the use of suitable head covering, and the
application of sun-blocking creams.

(iv)With respect to the proneness to middle ear infection and pneumonia,
prompt treatment of respiratory tract infections with antibiotics is advisable
to prevent permanent damage to the lungs (which in several cases has led to
chronic and disabling lung disease).

(v)The diabetes in BS is treated in standard ways, to avoid or delay that
diseases’s own set of serious complications.

(vi)With respect to the cancer proneness: Although as mentioned in (i), above]
its cause, the genomic instability, cannot be corrected, programs for cancer
surveillance can be devised and carried out with the help of a family physician
knowledgeable about BS. (The Registry, when asked, will provide physicians
with information about BS.) During childhood, when leukemia is the main
neoplasm arising, no special surveillance is indicated, at least at present.
In adulthood, however, extra attention is to be paid to seemingly unimportant
symptoms that might permit early diagnosis of so-called solid tumors, those
cancers that, for cure, usually depend on their prompt surgical removal.
Procedures in general use for early diagnosis of cancer such as mammography,
Pap smears, and colonoscopy may be begun earlier in life than usual. Because
bone marrow transplantation sometimes is useful in treating cancer of certain
types, early identification of a genetically compatible sib as a potential
marrow donor can be attempted; also, if future non-BS pregnancies occur, stem
cells can be harvested from the placental blood and stored frozen. In theory,
storage frozen of the affected person’s own bone marrow, withdrawn when he/she
is healthy, could be useful (and in one case has been); however, its secure
storage for many years presents major problems.

(vii)Many of those with BS require varying degrees of family protection
throughout their lives as result of a combination of factors foremost of which
is the significant handicap of small size, but also the facial skin lesion when
severe, chronic lung disease if present, and the poorly understood learning
disability.